2.1. Rhabdomyolysis and Renal Failure
In 1941, it was first noted that an association existed between skeletal muscle injury and the release of muscle cell contents into plasma (Bywaters and Beall, Br. J. Med. 1:427-432, 1941). This release of muscle cell contents (rhabdomyolysis) includes myoglobin, resulting in myoglobinemia and myoglobinuria, or myoglobin in the urine. In its most serious manifestation, rhabdomyolysis may ultimately result in acute renal failure (ARF). Rhabdomyolysis is not solely associated with direct muscle trauma or renal failure; the condition may be associated as well with non-traumatic causes such as prolonged strenuous exercise. Thus, myoglobinuria has also been shown to be connected with non-pathological conditions. It is estimated that about one-third of the patients with rhabdomyolysis will develop acute renal failure (Gaben et al. Medicine 61: 141-152, 1982). A list of a number of the possible causes for rhabdomyolysis provided in Table 1.
The exact mechanism by which ARF results from rhabdomyolysis has not yet been elucidated. The observed clinical association of ARF with intravascular hemolysis and skeletal muscle necrosis has led to the suggestion that the constituents of these tissues are toxic to the kidneys. Studies of the heme components in particular, i.e., myoglobin, hemoglobin and their derivations, have shown them to be extremely nephrotoxic when renal ischemia or systemic acidosis occurs.
The most commonly used model of myoglobinuric renal failure is produced by the subcutaneous or intramuscular injection of hypertonic glycerol (Hofstetter et al., in Acute Renal Failure, Brenner et al., eds., W. B. Saunders, p. 109, 1983). Following glycerol administration, muscle cell necrosis and myoglobinuria occur; in the early stages of ARF, there is a pronounced drop in renal blood flow (RBF), and a concomitant rise in renal vascular resistance. Also observed in the early phase of glycerol induced ARF is a fall in glomerular filtration rate. In the maintenance phase, although RBF may return to normal because of fluid expansion, GRF does not necessarily improve, indicating that its fall at this stage is not necessarily associated with the drop in RBF. The mediation of renal vasoconstruction in myoglobinuria ARF have not been established; the renin-angrotensive system haa been suggested, based on the observation that salt-loaded animals are resistant to glycerol-induced ARF. However, administration of an angrotensin II antagonist, or an angrotensin converting enzyme inhibitor, although effective in raising RBF, has little effect on blood urea nitrogen levels (BUN). Other vaso-active systems, such as prostaglandin, arginine, vasopressin and endotoxin, a component of the cell wall of gram negative bacteria have been indicated as possible contribution to the renal ischemia associated with rhabdomyolysis-myoglobinuric ARF. Alterations in glomerular capillary ultrafiltration coefficient may also be an early pathogenic effect in ARF, but no conclusive results have yet been observed. Thus, despite the intensive study directed in this area, the actual pathogneic mechanism which causes a drop in GRF is still unknown.
TABLE 1 ______________________________________ Causes of Rhabdomyolysis ______________________________________ Increased Energy Consumption Primary-muscle Injury Exercise stress Polymyositis Amphetamine, LSD Dermatomyositis Delirium tremens Trauma, crash Convulsions Burns High-voltage shock Infectious Tetanus Gas gangrene Succinylcholine chloride Tetanus Fever Leptospirosis Malignant Hyperpyrexia Viral influenza Exercise-Induced heat stroke Coxsackie infection Heat cramps Shigellosis Decreased Energy Herbicola lathyri bacteremia Production-Genene Reye's syndrome Affecting Carbohydrate Septic shock Metabolism Myxoma virus Myophosphorylase deficiency Pseudomonas bacteremia .alpha.-glucosidase deficiency Miscellaneous Amylo-1,6-glucosidase Venom deficiency Snake bite Phosphohexoisomerase Hornet deficiency Household brown spider Phosphofructokinase Sea-snake poisoning deficiency Drugs Cytochrome Disturbances Heroin Diabetic acidosis Barbiturates Nonketotic hyperosmolar coma Propoxyphene Affecting Lipid Metabolism Methadone Carnitine deficiency Glutethimide Carnitine pulmityltansference Amphetamines deficiency Plasmocid Various muscular dystrophies Licorice (glycyrrhizate) .dwnarw.Energy Production Acquired Carbenoxolone K deficiency Amphotericin-B .dwnarw.Glycogen formation Diazepam .dwnarw.Insulin release with Codeine hyperglycemia Epsilon aminocuprioc acid Ethanol Peanut oil (arachidonic acid) Myxedema Phencyclidine Hypothermia Other Hypophosphatemia Ingestion of quail fed on hemlock Diabetic ketoacidosis seed or sweet parsley .dwnarw.Oxygenation Isopropyl alcohol .dwnarw.Muscle blood flow Ethylene glycol K deficiency Huff disease McArdle syndrome Calciphylaxis (azotemic Postural vascular occlusion hyperparuthyroidism) Arterial embolism Acute schizophrenia Prolonged surgery-(open Hypernatremia heart) Insomnia Carbon monoxide 2,4-dichlorophenoxyacetic acid Shock Magnesium deficiency Trauma Crash syndrome Conga drums Firearm recoil Karate Ice skating Jackhammer Sickle-cell trait ______________________________________
A number of conditions in which some form of tissue injury is observed have been suggested as being mediated by reactive oxygen metabolitis, including free radical species (see, e.g. Band et al., Am. J. Physiol. 251: F-765-F776, 1986; Weiss et al., Lab. Invest. 47: 5-18, 1982; Fantone et al., Human Pathol 16: 973-978, 1985; Weiss, Acta Physiol. Scand. 548: 9-37, 1986). Certain in vivo studies have demonstrated a protective effect of hydroxyl radical scavengers and/or iron chalatons in several models of tissue injury (Fox J. Clin. Invest. 74: 1456-1464, 1984; Trill et al., Am. J. Pathol. 119: 376-384, 1985; Take et al., Am. Rev. Rsp. Dis. 126: 802-806, 1982; Ward et al., J. Clin Invest. 76: 517-527, 1985; Ward et al., J. Clin. Invest. 72: 789-901, 1983; Flegrel et al., Am. J. Physiol. 115, 375-382, 1984; Johnson et al., Lab. Invest. 54: 499-506, 1986). Studies performed in connection with the present invention now suggest that reactive oxygen metabolites may play an important role in the pathology of rhabdomyolysis associated acute renal failure.